EP0431371A1 - 3-Aminopyrroles, procédé pour leur préparation et leur utilisation comme médicaments - Google Patents

3-Aminopyrroles, procédé pour leur préparation et leur utilisation comme médicaments Download PDF

Info

Publication number
EP0431371A1
EP0431371A1 EP19900121958 EP90121958A EP0431371A1 EP 0431371 A1 EP0431371 A1 EP 0431371A1 EP 19900121958 EP19900121958 EP 19900121958 EP 90121958 A EP90121958 A EP 90121958A EP 0431371 A1 EP0431371 A1 EP 0431371A1
Authority
EP
European Patent Office
Prior art keywords
methoxycarbonyl
general formula
tolyl
phenyl
ethoxycarbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP19900121958
Other languages
German (de)
English (en)
Other versions
EP0431371B1 (fr
Inventor
Jürgen Dr. sc. Liebscher
Alexander Dr. Knoll
Alexej Dr. Uschmajew
Andreas Dipl.-Chem. Rolfs
Dieter Dr. Sc. Lohmann
Gottfried Dr. Faust
Eveline Dr. Morgenstern
Peter Dr. Scharfenberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AWD Pharma GmbH and Co KG
Original Assignee
Arzneimittelwerk Dresden GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arzneimittelwerk Dresden GmbH filed Critical Arzneimittelwerk Dresden GmbH
Publication of EP0431371A1 publication Critical patent/EP0431371A1/fr
Application granted granted Critical
Publication of EP0431371B1 publication Critical patent/EP0431371B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to 3-aminopyrroles, processes for their preparation and their use as medicaments or medicaments.
  • the invention can be used in the pharmaceutical industry and in human medicine.
  • 3-aminopyrroles which carry aminocarbonyl (DE 2 605 419) or carbonyl groups (US 4 198 502) in the 4-position have been classified as CNS-active substances. This effect is specifically called sedative and analgesic, but has not been proven by any test results.
  • These compounds were synthesized by modifying aminopyrrole derivatives, which in turn were obtained from ⁇ -aminonitriles and ⁇ -dicarbonyl compounds (DE 2 605 419, DE 2 439 284, DE 2 462 967, DE 2 462 966, DE 2 462 963, GB 1 492,663, U.S. 4,198,502).
  • 3-Amino-2,4-diphenylpyrrole is formed when phenacylamine condenses with itself [p. Gabriel: Ber. dtsch. Chem. Ges. 41 (1908) 1127].
  • the known processes do not describe any 3-amino-4-arylpyrroles substituted on the amino group, which have an anticonvulsant effect.
  • the substituent variability of the known methods is severely restricted.
  • the known anticonvulsants have the disadvantage of undesirable side effects (e.g. neurotoxicity).
  • the object of the invention is to develop new CNS-active 3-aminopyrroles, in particular those which have anticonvulsant or analgesic properties, to develop processes for their preparation and to use them as medicaments or as medicaments.
  • the aim is to reduce side effects, e.g. B. to achieve a lower neurotoxicity than with the currently common anticonvulsants.
  • R1 is hydrogen, an unsubstituted or substituted alkyl, an unsubstituted or substituted cycloalkyl, aralkyl, an unsubstituted or substituted aryl or heteroaryl radical, an acyl, alkoxycarbonyl, an N-un, N-mono- or N, N-disubstituted aminocarbonyl or a Aminothiocarbonyl
  • R2 hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, an N-un, N-mono- or N, N-disubstituted aminocarbonyl, an unsubstituted or substituted aryl or heteroaryl radical, a cyano or nitro group
  • R3 is hydrogen,
  • 3-aminopyrroles of the general formula I are, for example, 4-arylpyrrolecarboxylic acid esters which are substituted in the 3-position with morpholino, piperazino, 4-alkylpiperazino, piperidino, pyrrolidino, dimethylamino, diethylamino, diethanolamino or di- ( ⁇ -alkoxyethyl) amino.
  • Processes for the preparation of 3-aminopyrroles of the general formula I are also specified according to the invention.
  • 3-aminopyrroles of the general formula I by cyclization of a trimethinium salt of the general formula IV with the meaning explained for R1, R2, R3, R4 or R3, R4, R5 and R6 or R5 / R6, in which R7 is an alkyl or aralkyl group and Y- is an acid residue such as a halide.
  • Perchlorate an alkyl sulfate, a sulfonate, sulfate, tetrafluoro or tetraaryl borate or picrate, or optionally the associated free base of a trimethinium salt of the general formula IV or a trimethinium salt of the general formula V with the meaning explained for R1, R2, R3, R4 or R3 / R4, R5, R6 or R5 / R6, in which X1 is a leaving group, for example a halogen, an alkoxy or an amino group and Y- is an acid residue anion, such as a halide, perchlorate, an alkyl sulfate, a sulfonate, sulfate, tetrafluoro- or tetraarylborate or picrate, or optionally the associated free base of a trimethinium salt of the general formula V, preferably with a base.
  • an acrylic acid amide derivative of the general formula VI with the meaning explained for R3, R4 or R3 / R4, R5, R6 or R5 / R6, in which X2 is an oxygen, sulfur or mono- or disubstituted nitrogen atom and Y1 is a leaving group, such as a substituted or unsubstituted amino group , an alkylthio, an alkoxy, a hydroxy, a mercapto, an acyloxy group or a halogen, or an iminium salt of the general formula VIII with the meaning explained for R3, R4 or R3 / R4, R5, R6 or R5 / R6, in which X3 and Y1 are the same or different for a leaving group, such as a substituted or unsubstituted amino group, an alkylthio, an alkoxy, an Hydroxy, a mercapto, an acyloxy group or a halogen, and Z- for
  • 3-aminopyrroles of the general formula I with the meaning explained for R1, R2, R3, R4 or R3 / R4, R5 and R6 or R5 / R6 are furthermore reacted by reacting an enamine derivative of the general formula XIII with the meaning explained for R1, R3, R4 or R3 / R4, R5 and R6 or R5 / R6, in which X3 represents a leaving group, for example an alkoxy, alkylmercapto or substituted amino group or a halogen, or a salt of an enamine derivative of the general formula XIII, such as, for example, a hydrohalide, a hydroperchlorate, a hydrosulfonate or a hydrotetrafluoroborate, with an alkylating agent of the general formula XIV R2CH2Z3 XIV with the meaning explained for R2, in which Z3 represents a leaving group, for example a halogen, a sulfonate, an alkyl sul
  • 3-aminopyrroles of the general formula I with the meaning explained for R1, R2, R3, R4 or R3 / R4, R5 and R6 or R5 / R6 are also obtained in that an enamine of the general formula XV with the meaning explained for R1, R2, R5 and R6 or R5 / R6 with an iminium salt of the general formula XVI with the meaning explained for R3 and R4 or R3 / R4, in which Y3 and Y4 are the same or different leaving groups, such as chlorine, amino groups, alkyl mercapto or alkoxy groups, and Y is an acid residue, for example a halide, a sulfonate, a sulfate or a Trifluoroacetate, represent and optionally reacted with a base.
  • an amine, an alkali or alkaline earth hydroxide or hydride, an alkali carbonate or a metal amide can be used as the base, for example.
  • 3-aminopyrroles of the general formula I as above with the meaning explained for R1, R2, R3, R4 or R3 / R4, R5 and R6 or R5 / R6 can also be obtained in that a 3-substituted pyrrole of the general formula XX with the meaning explained for R1, R2, R5 and R6 or R5 / R6, in which X4 represents a leaving group, such as a halogen, a hydroxyl or an alkoxy group, an alkylthio group or the diazonium group, with an amine of the general formula XI HNR3R4 XXI with the meaning explained for R3 and R4 or R3 / R4.
  • 3-aminopyrroles of the general formula I with those for R1, R3, R4 or R3 / R4, R5 and R6 or R5 / R6 explained meaning in which R2 is COOR7, where R7 is a substituted or unsubstituted alkyl radical, also by reacting a 3-aminopyrrolecarboxylic acid of the general formula XXII with the meaning explained for R1, R3, R4 or R3 / R4, R5 and R6 or R5 / R6 or a salt of a 3-aminopyrrolecarboxylic acid of the general formula XXII, for example a sodium, potassium or ammonium salt, with an alkylating agent of the general formula XXIII R7X5 XXIII with the meaning explained for R7, in which X5 represents a leaving group, for example a halogen or a sulfonyl group, and optionally with a base.
  • X5 represents a leaving group, for example
  • the compounds of the invention are, with the exception of the 4- (p-anisyl) -3-morpholinopyrrole-2-carboxylic acid methyl ester, the 3-morpholino-4-phenylpyrrole-2-carboxylic acid methyl ester and ethyl ester, the 3-morpholino-4- (p-tolyl ) -pyrrole-2-carboxylic acid methyl ester and ethyl ester as well as the 4- (p-chlorophenyl) -3-morpholinopyrrole-2-carboxylic acid methyl ester.
  • the compounds according to the invention show a high anticonvulsive effect in various cramp models and are characterized by low toxicity and, above all, a much higher protective index than currently known commercial anticonvulsants.
  • the anticonvulsant effect is surprising, since no such effect has been described in general for 3-aminopyrroles.
  • the new active ingredients can be converted in a known manner into customary pharmaceutical formulations, such as tablets, capsules, dragees, granules or solutions Use of inert, non-toxic, pharmaceutically suitable carriers or solvents.
  • a solution of 10 mmol of aminoacrylic acid derivative of the general formula II and 1.9 g of dimethyl sulfate or 2.2 g of methyl iodide in 20 ml of chloroform is heated under reflux for 15 minutes. After the solvent has been stripped off, the mixture is diluted with 10 ml of ethanol or methanol and 1 g of triethylamine is added to the mixture. The mixture is heated to boiling for 5 minutes and, after cooling, is diluted with a little water. The 3-aminopyrrole of the general formula I is filtered off and recrystallized.
  • a suspension of 10 mmol of aminoacrylic acid derivative of the general formula II in 10 ml of water is added dropwise with cooling with 30 mmol of 30% hydrogen peroxide, so that the temperature remains below 20 ° C.
  • the mixture is left to react for 30 minutes at room temperature and then cooled to 5 ° C.
  • the solid product is filtered off and mixed with 10 ml of acetonitrile and 2 ml of triethylamine.
  • the mixture is heated to boiling for 30 minutes and, after cooling, diluted with a little water.
  • the end product of the general formula I is filtered off and recrystallized.
  • the mixture is stirred vigorously for 5 hours at room temperature.
  • the mixture is then neutralized with dilute hydrochloric acid, the organic phase is separated off and the aqueous phase is extracted twice with methylene chloride.
  • the combined organic extracts are washed with water and potassium carbonate solution. After drying over sodium sulfate, the solvent is evaporated off.
  • the end product of the general formula I crystallizes in Add a little methanol or cyclohexane.
  • the mixture is warmed on the boiling water bath for 30 minutes and then 3 ml of triethylamine are added.
  • the mixture is heated under reflux for 30 minutes. After cooling, pour on ice.
  • the end product of the general formula I is filtered off and recrystallized.
  • mice By infusion of 100 mg / kg pentetrazole (infusion rate 36 ml / h) through the tail vein, clonic convulsions (myoclonal twitches) first appear in mice (KM 18-22 g).
  • the prolongation of the infusion time (in s) up to the occurrence of the convulsions in comparison to control animals is regarded as an increase in the pentetrazole spasm threshold and thus as an anticonvulsant effect of the tested substances.
  • Results Compound I-12: ip at 5.10 ⁇ 4 mol / kg: 20.4% increase in the seizure threshold
  • Compound I-10 ip at 5.10 ⁇ 4 mol / kg: 19.4% increase.
  • mice receive the substances to be tested in doses of 5.10 ⁇ 4, 10 ⁇ 3 and 5.10 ⁇ 3 mol / kg KM. The lethality of the animals is determined 24 hours after application. Results: Compound I-6: oLD greater than 5.10 ⁇ 3 mol / kg Compound I-22: oLD greater than 5.10 ⁇ 3 mol / kg.
  • mice KM 18-22 g are placed on a hot plate at 56 ° C. 30 minutes after administration of the test substances, and the reaction time to this thermal pain stimulus is determined. An extension of the reaction time of substance-treated animals compared to control animals is considered an analgesic effect.
  • mice With ip administration of 0.6% acetic acid, abdominal cramps (writhings) are triggered in mice (KM 18 - 22 g). Reduk serves as a measure of the potency of a substance tion of the number of writhing reactions in treated animals compared to the control group. In addition to analgesic compounds, various CNS-active compounds also reduce the number of writhings. Results: Compound I-2: po at 10 ⁇ 3 mol / kg: 71.3% inhibition Compound I-6: po at 10 ⁇ 3 mol / kg: 84.2% inhibition at 10 ⁇ 4 mol / kg: 50.2% inhibition. Comparative value: Analgin: po at 10 ⁇ 4 mol / kg: 50% inhibition.
  • Trained mice (KM 18 - 22 g) are placed on the torsion bar (5 revolutions / min) for 1 min after substance application.
  • the premature falling off the torsion bar is a measure of a substance effect.
  • the protective index is the quotient of TB50 / ED50 MEK.
  • 3-aminopyrrole of the general formula I is suspended in the required amount in polyethylene glycol and in a gelatin mixture of the composition Gelatin 1 part by mass Glycerol 5 parts by weight Water 2 parts by mass incorporated.
  • a mixture is made with the following ingredients: Lactose 5 parts by weight Potato thickness 5 parts by mass Magnesium stearate 1 part by mass.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP90121958A 1989-11-17 1990-11-16 3-Aminopyrroles, procédé pour leur préparation et leur utilisation comme anticonvulsifs Expired - Lifetime EP0431371B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DD89334670A DD298912A5 (de) 1989-11-17 1989-11-17 Verfahren zur herstellung von 3-aminopyrrolen
DD334670 1989-11-17

Publications (2)

Publication Number Publication Date
EP0431371A1 true EP0431371A1 (fr) 1991-06-12
EP0431371B1 EP0431371B1 (fr) 1997-09-10

Family

ID=5613902

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90121958A Expired - Lifetime EP0431371B1 (fr) 1989-11-17 1990-11-16 3-Aminopyrroles, procédé pour leur préparation et leur utilisation comme anticonvulsifs

Country Status (10)

Country Link
US (2) US5502051A (fr)
EP (1) EP0431371B1 (fr)
JP (1) JPH07113015B2 (fr)
DD (1) DD298912A5 (fr)
DE (1) DE59010759D1 (fr)
ES (1) ES2108005T3 (fr)
FI (1) FI102169B1 (fr)
HU (1) HUT56343A (fr)
RU (2) RU2120796C1 (fr)
YU (1) YU48469B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0583561A2 (fr) * 1992-08-20 1994-02-23 ARZNEIMITTELWERK DRESDEN GmbH Procédé pour la préparation de 3-aminopyrroles 1-nonsubstitués
WO1998004262A1 (fr) * 1996-07-25 1998-02-05 Arzneimittelwerk Dresden Gmbh Prophylaxie et therapie des sequelles d'un defaut d'irrigation sanguine cerebrale et de maladies neurodegeneratives

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5792778A (en) * 1995-08-10 1998-08-11 Merck & Co., Inc. 2-substituted aryl pyrroles, compositions containing such compounds and methods of use
US5837719A (en) * 1995-08-10 1998-11-17 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
WO1997016441A1 (fr) * 1995-10-31 1997-05-09 Merck & Co., Inc. Pyrroles aryliques de substitution, compositions renfermant de telles composes et methodes d'utilisation de ces substances
US5908858A (en) 1996-04-05 1999-06-01 Sankyo Company, Limited 1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses
US5776954A (en) * 1996-10-30 1998-07-07 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
US7122666B2 (en) * 1999-07-21 2006-10-17 Sankyo Company, Limited Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses
BRPI0814542A2 (pt) 2007-07-12 2014-09-30 Tragara Pharmaceuticals Inc Métodos e composições para o tratamento de câncer, tumores e desordens relacionadas a tumores
WO2015039073A1 (fr) 2013-09-16 2015-03-19 Kellogg Glen E Pyrroles polysubstitués ayant des activités de rupture de microtubules, cytotoxiques et antitumorales et méthodes les utilisant

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0249236A1 (fr) * 1986-06-13 1987-12-16 Warner-Lambert Company Dérivés de N-1H-tétrazolyl-5-yl-(cycle à 5 chaînons)-carboxamide, leur procédé de préparation et leur application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4198502A (en) * 1973-08-22 1980-04-15 Gruppo Lepetit S.P.A. Aminopyrrole derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0249236A1 (fr) * 1986-06-13 1987-12-16 Warner-Lambert Company Dérivés de N-1H-tétrazolyl-5-yl-(cycle à 5 chaînons)-carboxamide, leur procédé de préparation et leur application

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0583561A2 (fr) * 1992-08-20 1994-02-23 ARZNEIMITTELWERK DRESDEN GmbH Procédé pour la préparation de 3-aminopyrroles 1-nonsubstitués
DE4227479A1 (de) * 1992-08-20 1994-02-24 Dresden Arzneimittel Verfahren zur Herstellung von 1-unsubstituierten 3-Aminopyrrolen
EP0583561A3 (en) * 1992-08-20 1994-07-06 Dresden Arzneimittel Process for the preparation of 1-unsubstituted 3-aminopyrroles
US5414082A (en) * 1992-08-20 1995-05-09 Arzneimittelwerk Dresden Gmbh Method for producing 1-unsubstituted 3-aminopyrroles
WO1998004262A1 (fr) * 1996-07-25 1998-02-05 Arzneimittelwerk Dresden Gmbh Prophylaxie et therapie des sequelles d'un defaut d'irrigation sanguine cerebrale et de maladies neurodegeneratives

Also Published As

Publication number Publication date
YU217390A (sh) 1993-05-28
FI102169B (fi) 1998-10-30
US5502051A (en) 1996-03-26
EP0431371B1 (fr) 1997-09-10
RU2120796C1 (ru) 1998-10-27
DD298912A5 (de) 1992-03-19
ES2108005T3 (es) 1997-12-16
US5684160A (en) 1997-11-04
YU48469B (sh) 1998-08-14
FI102169B1 (fi) 1998-10-30
JPH07113015B2 (ja) 1995-12-06
FI905689A (fi) 1991-05-18
RU2060991C1 (ru) 1996-05-27
DE59010759D1 (de) 1997-10-16
FI905689A0 (fi) 1990-11-16
HU907176D0 (en) 1991-05-28
JPH03271271A (ja) 1991-12-03
HUT56343A (en) 1991-08-28

Similar Documents

Publication Publication Date Title
DE1695556C3 (de) 3-Alkyl-1,2,3,4,4a,9-hexahydropyrazino[1,2-f]morphanthridinderivate
DE19834045A1 (de) (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin
DE3346573A1 (de) 1,3,4,5-tetrahydrobenz(c,d)indole, ein verfahren zu ihrer herstellung und ihre verwendung
EP0000220B1 (fr) Dihydrouraciles, procédé pour leur préparation et médicaments les contenant
EP0431371B1 (fr) 3-Aminopyrroles, procédé pour leur préparation et leur utilisation comme anticonvulsifs
DE2505297A1 (de) Neue 2-arylamino-2-imidazolinderivate und ein verfahren zu deren herstellung
DE3152071C2 (de) Taurinderivate, deren Herstellung und Verwendung in Arzneimitteln
DE2362754C2 (de) Cyclopropylalkylaminoreste enthaltende Oxazolinverbindungen, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
EP0557879A1 (fr) 4-amino-2-uréido-5-pyrimidine carboxamide, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
AT396362B (de) 5,5-dimethyl-3-phenylvinyl-1-aminoalkoxy-iminocyclohex-2-enderivate
DE3233424A1 (de) Isochinolinderivate, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung
CH626892A5 (fr)
DE1518452B2 (de) 4-substituierte 2-benzhydryl-2butanol-derivate und verfahren zu ihrer herstellung
DE3031703C2 (fr)
DD298913A5 (de) Verfahren zur herstellung von n-substituierten 3-aminopyrrolen
DE3028064C2 (fr)
DE2406490C2 (de) 1,4-Dihydro-3(2H)-isochinolinonverbindungen und ihre Salze, Verfahren zur Herstellung derselben und diese Verbindungen enthaltende Arzneimittel
DE69230110T2 (de) An drei ringen substituierte tetrahydropyridin-derivate
DE3242442A1 (de) Benzylidenderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
AT390791B (de) Verfahren zur herstellung neuer kondensierter as-triazinium-derivate sowie von deren isomeren
DE69405999T2 (de) Pharmazeutisch wirksame enantiomere
DE3423003A1 (de) Benzo(c)(1,8)naphthyridine, verfahren zu ihrer herstellung und ihre verwendung sowie diese verbindungen enthaltende zubereitungen
DE2029991C3 (de) 2-Hydroxy-5-aminobenzamide, Verfahren zu ihrer Herstellung und Arzneimittel, die diese Verbindungen enthalten
DE2215999A1 (de) Nitroimidazolyl-triazolo-pyridazine und verfahren zu ihrer herstellung
DD298918A5 (de) Verfahren zur herstellung von 3-aminopyrrolderivaten

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE ES FR GB IT LI NL SE

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SCHARFENBERG, PETER, DR.

Inventor name: MORGENSTERN, EVELINE, DR.

Inventor name: FAUST, GOTTFRIED, DR.

Inventor name: LOHMANN, DIETER, DR. SC.

Inventor name: ROLFS, ANDREAS, DIPL.-CHEM.

Inventor name: USCHMAJEW, ALEXEJ, DR.

Inventor name: KNOLL, ALEXANDER, DR.

Inventor name: LIEBSCHER, JUERGEN, DR. SC.

17P Request for examination filed

Effective date: 19911121

17Q First examination report despatched

Effective date: 19930917

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ARZNEIMITTELWERK DRESDEN GMBH

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): BE CH DE ES FR GB IT LI NL SE

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: MICHELI & CIE INGENIEURS-CONSEILS

Ref country code: CH

Ref legal event code: EP

ITF It: translation for a ep patent filed
GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 19970912

REF Corresponds to:

Ref document number: 59010759

Country of ref document: DE

Date of ref document: 19971016

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2108005

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20011024

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20011026

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20011029

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20011102

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20011106

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20011115

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20011116

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20011119

Year of fee payment: 12

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021116

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021117

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021117

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021130

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20021130

BERE Be: lapsed

Owner name: ARZNEIMITTELWERK *DRESDEN G.M.B.H.

Effective date: 20021130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030603

EUG Se: european patent has lapsed
GBPC Gb: european patent ceased through non-payment of renewal fee
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030731

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20030601

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20031213

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20051116